Peripheral nerve is the pathway through which sensory information is conveyed from the periphery to the central nervous system (CNS), and commands for movement are conveyed from the CNS to muscle. Peripheral nerve injury results in the loss of both feeling and movement. As peripheral axons regenerate they often enter inappropriate pathways, leading cutaneous axons to muscle and motor axons to skin. As a result of this and other limiting factors, only 10% of adults will experience restoration of near-normal function after peripheral nerve repair. The goal of this proposal is to improve the outcome of peripheral nerve injury. Preferential Motor Reinnervation (PMR), the tendency for motor axons regenerating in mixed nerve to return to muscle, is the starting point for our specific aims. Aim I explores the mechanism underlying PMR. Although pruning of motor axon collaterals from incorrect pathways leads to early PMR, motor axons that regenerate more slowly appear to recognize motor pathways directly. Understanding the mechanism by which this occurs could help us design strategies to improve specificity and therefore outcome. This aim also uses mice engineered to express fluorescent protein in their neurons to evaluate the behavior of motor axons as they explore the distal stump. Their response to different environments should provide morphologic evidence of pathway recognition and/or pruning behavior. Aim II focuses on the effects of electrical stimulation, which enhances both sensory and motor regeneration. This aim will define the types of neuron in the DRG that are affected by stimulation, and determine the specificity with which these neurons reinnervate muscle vs. skin. The aim will also explore clinically important questions regarding the timing, duration, and functional consequences of stimulation, and use the fluorescent mice to define the morphology of stimulated axons. Aim III Investigates the possibility that degenerating sensory and motor nerve may preferentially support the regeneration of sensory or motor axons respectively. Motor axons have responded differently to cutaneous and muscle pathways in previous experiments, and recent PCR studies have provided evidence of differential upregulation of trophic factors in degenerating dorsal and ventral root. Fresh and predegenerated ventral root will be evaluated as graft for sensory and motor axons, and differential expression of trophic factors in dorsal and ventral roots will be further elaborated. [unreadable] [unreadable]